1. Tulane National Primate Research Center, Covington, Louisiana 70433, USA
2. Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021, USA
3. St George's, University of London, London SW17 0RE, UK
4. Department of Biochemistry, Weill Medical College of Cornell University, New York, New York 10021, USA
5. Bristol-Myers Squibb Pharmaceutical Institute, Wallingford, Connecticut 06492, USA
6. Merck Research Laboratories, Rahway, New Jersey 07065, USA

Correspondence to: John P. Moore² Correspondence should be addressed to J.P.M. (Email: jpm2003@med.cornell.edu); see Supplementary Information for details about requests for materials.

Human immunodeficiency virus type 1 (HIV-1) continues to spread, principally by heterosexual sex, but no vaccine is available¹. Hence, alternative prevention methods are needed to supplement educational and behavioural-modification programmes. One such approach is a vaginal microbicide: the application of inhibitory compounds before intercourse². Here, we have evaluated the microbicide concept using the rhesus macaque 'high dose' vaginal transmission model with a CCR5-receptor-using simian–human immunodeficiency virus (SHIV-162P3) and three compounds that inhibit different stages of the virus–cell attachment and entry process. These compounds are BMS-378806, a small molecule that binds the viral gp120 glycoprotein and prevents its attachment to the CD4 and CCR5 receptors^{3, 4}, CMPD167, a small molecule that binds to CCR5 to inhibit gp120 association⁵, and C52L, a bacterially expressed peptide inhibitor of gp41-mediated fusion⁶. In vitro, all three compounds inhibit infection of T cells and cervical tissue explants, and C52L acts synergistically with CMPD167 or BMS-378806 to inhibit infection of cell lines. In vivo, significant protection was achieved using each compound alone and in combinations. CMPD167 and BMS-378806 were protective even when applied 6 h before challenge.

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